 The 2015 Palliative Care in Oncology Symposium concluded on October 10th, and one of the events that you co-chaired was the “Death CafÃ©,” where oncologists gathered to discuss the topic of death and dying in a safe, informal venue. Can you explain what the “Death CafÃ©” is, how it’s set up, and the goals of the gathering?

 The Death CafÃ© idea arose from work done by Swiss sociologist Bernard Crettaz, with the plan to get the public talking more about death, specifically each person’s own death or personal death experiences. The point was to come together in public with perfect strangers and over tea and cookies to talk about death with the goal of making it less foreign. This concept was initially used by the lay public and continues in this way, with many active Death CafÃ©s across the world. The Death CafÃ© is meant to be informal and non-rigid, and to allow very personal interchange on the subject of death. Since oncologists have very intimate relationships with patients who are dying, Dr. Daniel Hinshaw and I thought it would be helpful if oncologists had a chance to explore their own feelings and emotions around death. The Death CafÃ© was set up not to talk about our patients, but how having viewed death through our patients has altered our perceptions of our own deaths or the deaths of those near and dear to us.

What do you feel are the issues around death and dying that patients are most interested in talking to their doctors about?

 Each individual has different issues, so it is really important to raise the question about what death and dying means to that individual. It must be raised in a very caring and supportive way (eg, “Have you thought about dying?”; “What concerns you about dying?”), and it is important to actually use the “D” word, something most physicians have avoided in the past, as we have always viewed death as a failure on our part (see “Just Say Die” by Scott Berry, J Clin Oncol, 2008). Some common themes are present for many patients, including:

i. Not being a burden to their family/loved ones

ii. Not being abandoned (by the health care system, family, friends, community, etc)

vi. Finalizing relationships/mending fences

viii. Telling those you love that you love them

The other very important way that physicians can help dying patients is to guide them through the death process. Most people who are dying have never died before (I have never died before, either!), so they do not get an opportunity to practice. Physicians must take the lessons we have learned from those who have died well and those who have struggled with death, and help our patients navigate this phase of life. There is one concept I like to share with patients facing death, taken from work by Dr. Ira Byock-the five things it is often important to say to loved ones when dying:

When witnessing the deaths of others, particularly our patients, family members, and loved ones, it can in some sense be a “dress rehearsal” for our own deaths. Asking patients about their experience and perspective on serious illnesses they have previously witnessed may be another way to help them and family members as they face the possibility of an incurable cancer.

It is also very important to know if there are financial or legal matters that the patient needs to take care of before they die. One example I recently came across was a divorced mother who had custody of her only child and wanted to make sure the biological father did not get custody after her death. Because of this, she actually pursued aggressive treatments that may have actually hurt her more than helped just so she could get this matter through the courts before she died. This is why it is so important to be honest with patients about survival and outcomes-so they can accomplish their goals with whatever time they have left.

Do you think oncologists have enough experience and comfort discussing death honestly with their patients? If not, what do you think the obstacles and challenges are for clinicians who treat terminally ill patients?

 No. The physicians are all driven by a great desire to do their best for the patient, but most lack the training or mentorship to talk about death and dying properly. Part of the reason for this is that physicians often view the death of a patient as a personal failure. This is where work by Dr. Anthony Back and the Vital Talk (

) program can really help. We need to begin to teach physicians how to talk about this very early on in medical school and foster this skill as they go through training. The other big problem that oncologists face is that we can develop very intense and personal relationships with our patients, and their death can feel like losing a family member. So, physicians need to learn how to vent our emotions and loss, hopefully through programs like the Death CafÃ©, which can help us to process these difficult feelings.

Dr. Moynihan and the ONCOLOGY staff would like to thank Dr. Daniel Hinshaw for his additional consultation and review of this Q&A.

Dr. Moynihan has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. 

Articles

This interview discusses the importance of discussing end-of-life issues with patients.

Timothy Moynihan, MD, on ‘Death Cafés’ and the Importance of Discussing End-of-Life Issues With Your Patients

The ability to leverage the adaptive immune system to treat human cancers has been a goal of immunologists and oncologists dating back to the pioneering experiments of William Coley. The ideal immunotherapy should mobilize the immune system to clear an existing population of malignant cells, without damaging adjacent healthy cells, and remain active in the event of recurrence. In practice, these goals have yet to be fully realized, in part because of the difficulties associated with identifying targets of the antitumor immune response. However, the introduction of highly effective immunotherapeutics-such as immune checkpoint blockade-coupled with advances in gene sequencing, has changed the face of the field entirely. Recent evidence indicates that mutations unique to a given individual’s tumor may be the long–sought-after targets of effective antitumor immunity and may hold the key to the design of the next generation of immune-based therapeutics.

Descriptions of tumor antigens first appeared in the literature in the middle of the 20th century following observations of immune-mediated clearance of carcinogen-induced tumors in murine experimental models.[1-4] In the subsequent decades many tumor antigens have been identified, including developmental (carcinoembryonic antigen, WT1 [Wilms tumor 1]), lineage-specific (Melan-A/MART-1 [melanoma antigen recognized by T cells 1], prostatic acid phosphatase), and cancer/testis (MAGE-A [melanoma-associated antigens], NY-ESO-1, PRAME [preferentially expressed antigen in melanoma]) antigens, all of which are produced by genes overexpressed by malignant cells.[5] These antigens are easily identifiable and often shared among a cohort of subjects.[6,7] However, they are, by definition, “self” antigens and, like other “self” antigens, subject to immune tolerance.[8-11] Thus, the qualities that make these tumor antigens amenable to study may in turn limit their therapeutic utility.[12-15]

Recent advances in genetic sequencing technologies have facilitated the discovery of a new class of tumor antigen derived from somatic mutations, which we have termed 

.[16,17] MTAs are the product of nonsynonymous somatic variations randomly acquired by malignant cells as a result of deregulated progression through the cell cycle. Nonsynonymous somatic variations change protein sequence and function, facilitating the acquisition of traits associated with replicative advantage and tissue invasiveness.[18,19] Yet, when a nonsynonymous somatic variant is expressed and the variant sequence translated, the immune system may perceive the variant protein as “foreign” or “nonself” and respond to the cell as though it were infected with a pathogen.[20]

Notably, the likelihood of generating MTAs appears to be roughly proportional to the number of somatic mutations present within a given tumor.[21,22] However, the production of MTAs does not depend on the type of somatic variation. MTAs have arisen from substitutions, insertions, and deletions, as well as from larger structural rearrangements, such as duplications, inversions, and translocations. Nor does the production of MTAs depend on the oncologic significance of the instigating mutation. MTAs have arisen from both classic tumor suppressors and oncogenes, as well as from somatic mutations of unknown significance. Finally, the production of MTAs does not appear to depend on clinical characteristics of age, sex, and disease histology. MTAs have been identified in patients with multiple types of solid and hematologic malignancies.[23-37]

Evidence from both murine and human studies suggests that MTAs play a significant role in the endogenous adaptive immune response to tumors, as well as the induced adaptive immune response to tumors treated with cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) or programmed death 1 (PD-1) antagonists. Indeed, patients with melanoma or squamous-cell non–small-cell lung cancer who are treated with immune checkpoint blockade appear to stand a greater chance of clinical benefit as the burden of somatic mutations increases.[38-40] Furthermore, patients with tumors deficient in DNA mismatch repair, in which the number of somatic mutations can be multiple orders of magnitude greater than in tumors of comparable origin, also appear to fare significantly better when treated with immune checkpoint blockade.[41] However, prospective trials will be required to establish the utility of MTAs as predictive biomarkers. Given the considerable excitement brought about by these findings, as well as the ongoing development of therapeutic approaches that directly target MTAs, we will consider how these tumor antigens are identified, highlight deficiencies in current processes, and speculate as to how existing methods may be improved through further research.

The identification of somatic variations in tumors and, by extension, MTAs relies on the use of high-throughput sequencing (Figure 1).[42-44] Typically, material from both the tumor and a matched normal sample are sequenced in tandem.[45,46] Due to economic and technical considerations, sequencing efforts are restricted to the known protein-coding regions of the genome (exome). However, the use of targeted sequencing panels is not advised because this severely limits the ability to identify novel MTAs.

Sequencing experiments designed to identify MTAs are performed at higher coverage depths than are typically encountered in the literature. This is true with regard to the sequencing of tumor material, as well as material derived from matched normal samples. Sequence coverage depth is described in terms of the mean number of reads successfully realigned to targeted loci. However, the process by which the exome is enriched prior to sequencing can result in significant nonuniformity in coverage depth. To achieve acceptable mean coverage across all target loci, a mean sequence coverage depth of 150× may be required for normal samples.[47] When tumor samples are sequenced, coverage depths are typically doubled (300×) to account for additional confounders, including intrinsic tumor heterogeneity and contamination of tumor samples with material from stromal and/or other infiltrating cell types. These and other sources of bias may be reduced even further through random sampling of multiple, distinct regions of the tumor or through sequencing of circulating tumor material (cells, DNA).

MTAs are produced when a nonsynonymous somatic variant is expressed and the variant sequence is translated into protein. The targeting of MTAs derived from expressed variants can lead to therapeutic responses in vivo in animal models, but the utility of MTAs derived from nonexpressed variants has not been established.[42-44,48] DNA sequencing can be used to measure sequence variation; however, it does not provide a measure of gene expression. Quantifying expression eliminates nonexpressed variants that can confound downstream analysis. In addition, expression analysis through RNA sequencing, as opposed to array-based methods, directly determines transcript sequence and structure, which mitigates the requirement for accurate annotation of the transcriptome. Unfortunately, because of both biologic and technical variables, it is difficult to provide a general recommendation with regard to target depth for RNA sequencing experiments. However, depths in excess of 50 to 100 million reads per sample can be required to unambiguously resolve the sequence of variant-containing transcripts.

The technical details of DNA and RNA sequence analysis are beyond the scope of this article. However, we would like to emphasize that the choice of parameters used in sequence analysis can introduce systematic error into the results of these analyses. To overcome these issues, it is advisable to perform all analyses with extensively vetted combinations of bioinformatics tools.[49] It may also be advisable to use many such vetted combinations and to consider only those results arrived at by consensus.[50,51]

The final step in identifying MTAs further refines the list of expressed nonsynonymous variants and eliminates those that are unlikely to be immunologically relevant. This procedure has been the subject of a number of recent reviews and will not be exhaustively detailed here. Fritsch et al, van Buuren et al, Rajasagi et al, and Gubin et al provide comprehensive overviews of the methodology.[52-55] Briefly, computational tools are used to assess the variant protein sequence and to determine whether it will be presented by host major histocompatibility complex (MHC) class I or II molecules-surface receptors required for the initiation of a cellular adaptive immune response. It has been demonstrated that putative MTAs that are predicted to bind to MHC molecules by this method can lead to therapeutic responses in vivo.[42-44] However, the criteria used to make this distinction were developed for the infectious disease setting, and additional studies will be required to formally establish criteria for use in identifying MTAs. Finally, there is an urgent need for new animal models that can be used to evaluate MTA-specific therapeutic approaches in a manner that can be translated into studies performed in humans.

Much remains to be determined regarding the specific dose, schedule, and route of delivery of MTA-targeting immune-based therapeutics and the relative role of CD4- vs CD8-mediated immunity (Figure 2).[48] At present, a number of early-phase clinical trials are assessing MTA-targeting vaccines, and the preliminary results are encouraging.[56] Tumor-lysate–, peptide-, RNA-, and dendritic cell–based vaccine substrates are being studied, but the optimal choice of vaccine adjuvant remains to be determined. Trials currently underway have largely employed certain synthetic toll-like receptor ligands, which have been studied in other vaccination projects. However, adjuvants that target other innate immune pattern recognition receptors, including C-type lectin (CLR), nucleotide-binding oligomerization domain (NOD), RIG-I–like (RLR), and stimulator of interferon genes (STING) receptor pathways, remain viable, unstudied alternatives. The use of stimulatory hematopoietins, such as FMS-like tyrosine kinase 3 ligand and granulocyte-macrophage colony-stimulating factor (sargramostim), should also be considered.[57-59]

Evidence suggests that indirect targeting of MTAs through the use of vaccine adjuvants or oncolytic viruses injected or infused in situ or directly into the body of existing tumors may represent yet another approach to the stimulation of an MTA-specific immune response.[60,61] Preclinical work suggests that in situ vaccination may be used as a bridge to formal MTA-targeted vaccination for patients with advanced primary or recurrent disease, thus broadening the range of patient groups who are eligible to receive precision immune-based therapeutics.

Finally, it will be important to consider the use of MTA-targeted agents in conjunction with CTLA-4 and PD-1/programmed death ligand 1 antagonists (see Figure 2). Although combination approaches have not been formally tested in humans, preliminary evidence suggests that MTA-targeted approaches can boost existing MTA-specific responses and also provoke MTA-specific responses de novo.[56] Thus, combination therapy may serve as a safe and effective means of overcoming resistance to immune checkpoint blockade.[61]

At present much remains to be determined regarding the efficacy of MTA-specific immune-based therapeutics, used individually or in combination with other therapeutics. Generating these data will require innovative prospective trial designs compatible with the degree of subject-to-subject variability inherent to this approach. However, because of the abundance of promising preclinical and early-phase clinical data, many in the field are initiating such trials, making the MTAs an exciting new class of targets in cancer immunotherapy.

Dr. Bhardwaj is a cofounder of Check Point Sciences. The other authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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Because of the abundance of promising preclinical and early-phase clinical data, mutation-derived tumor antigens an exciting new class of targets in cancer immunotherapy.

Mutation-Derived Tumor Antigens: Novel Targets in Cancer Immunotherapy

Hepatitis B virus (HBV) infection is common across the world. Infection can lead to significant morbidity from cirrhosis and hepatocellular carcinoma. An estimated 240 million people have chronic (hepatitis B surface antigen [HBsAg]-positive) HBV infection.[1] As a result of increasing immigration from highly endemic areas (eg, China, Southeast Asia, Africa, Eastern Europe), the prevalence of chronic infection in the United States is rising and is estimated to be 1.5 million.[2] Across the country, the overall age-adjusted prevalence of chronic infection and evidence of exposure to infection (defined by the presence of antibody to HBV core antigen [anti-HBc] in the absence of HBsAg) have been reported to be 0.3% and 4.7%, respectively[3]; however, rates are much higher and can approach 10% to 15% in certain cities. In addition, many patients with HBV infection are unaware that they are infected.[4,5] At the same time, it is estimated that over 40% of the US population will develop some type of cancer during their lifetime,[6] and most patients will receive immunosuppressive therapy (IST) as treatment for their malignancy. This is notable because patients with chronic HBV infection or evidence of prior HBV infection who are exposed to IST are at risk for HBV reactivation.[7,8] We will discuss HBV reactivation in order to raise awareness of the problem and to detail our strategy for preventing this potentially severe complication of IST.

Screening patients for HBV and intervening with appropriate antiviral prophylaxis prior to IST prevents HBV reactivation and its morbid sequelae. The definition of HBV reactivation varies, but we define viral reactivation as the reappearance of detectable HBV DNA that had been previously undetectable, or a positive HBsAg and HBV DNA level > 10,000 IU/mL in a previously unscreened patient. HBV can lead to hepatitis, which is defined as a threefold increase in alanine aminotransferase from baseline value. Hepatitis may then lead to impairment of liver function, liver failure, and death.[7,9] HBV reactivation can result in delay or termination of curative oncologic treatment, which may increase a patient’s risk of mortality.[10]

There is variability in the approach to HBV screening before cancer therapy. Some national guidelines[5,11] encourage universal screening of patients receiving cytotoxic therapy or IST, whereas others[12,13] support risk-based screening. Our current approach at Memorial Sloan Kettering Cancer Center (MSKCC) is to screen all new patients who will be receiving IST. Although certain patients may have a higher pre-test probability of a positive screening result (based on country of birth, sexual history, and blood transfusion, among other factors), our past experience at MSKCC has shown that at least half of HBV reactivations occurred in patients considered to be “low risk” for HBV infection; therefore, individualized risk-based screening would have missed these patients. Although HBV reactivation was initially described in lymphoma patients and best documented in HBsAg-positive patients treated with IST for hematologic malignancies,[14,15] the risk is not confined to this group; patients with solid tumors have also had documented HBV reactivation.[10,16,17] B-cell–depleting therapies and hematopoietic stem cell transplant (HSCT) are associated with higher risk of HBV reactivation.[8,18-21] For example, patients with previous exposure to HBV can also experience HBV reactivation when receiving rituximab-based therapy.[22-24] HBV reactivation can occur anytime during and for at least 12 months after completion of IST in certain patient populations.[25,26]

After a thorough review of the literature and society guidelines,[12,13] our approach is to screen by testing for HBsAg and anti-HBc, with reflexive testing of HBV DNA by polymerase chain reaction (PCR) in patients with positive results on either test. A small proportion of patients with exposure to HBV alone can have circulating DNA, and they appear to be at higher risk for HBV reactivation than patients who are anti-HBc–positive with negative PCR results. Patients who are HBsAg-positive or have detectable hepatitis B (HB) viral load (VL) receive oral entecavir 0.5 mg daily through the course of chemotherapy and for at least 6 months after the completion of cancer treatment. In addition, patients who are HBsAg-negative/anti-HBc–positive with undetectable HB VL are given entecavir prophylaxis prior to anti-CD20 therapy or before undergoing HSCT. Otherwise, patients positive for anti-HBc alone undergo monitoring of HB VL every 3 months, with prompt administration of entecavir if the VL becomes detectable.

For patients who are HBsAg-positive/anti-HBc–positive, there is a well-documented role for antiviral prophylaxis during treatment of hematologic and solid tumor malignancies.[27-31] Although lamivudine is inexpensive and well-studied in the prophylactic setting, breakthrough treatment resistance is a problem, both with short- and long-term use.[32-34] Entecavir and tenofovir are potent HBV inhibitors with a high barrier to resistance and are therefore first-line agents. A recent randomized controlled trial found that when compared with lamivudine, entecavir significantly reduced the rate of HBV reactivation (6.6% vs 30%; 

 = .001) and HBV-related hepatitis (0% vs 13.3%; 

 = .003).[35] Patients undergoing anti-CD20 therapy or HSCT who have had prior HBV exposure also benefit from antiviral prophylaxis. Huang et al conducted a randomized controlled trial that compared entecavir prophylaxis-starting before, during, and for 3 months after completion of chemotherapy-with deferred treatment (control group). During a mean 18-month follow-up period, 1 (2.4%) of 41 patients taking entecavir prophylaxis developed HBV reactivation compared with 7 (17.9%) of 39 control patients (

 = .027). No patients developed HBV-related liver decompensation or mortality in this study.[36]

Prophylaxis is maintained for at least 6 months after the completion of chemotherapy. Some guidelines recommend continuation for at least 12 months in patients receiving anti-CD20 therapy and HSCT.[12,13] The longer duration recommendation is a result of the discovery of HBV flares occurring up to 12 to 17 months after the last anti-CD20 dose.[36,37] This is certainly an area for further study.

The incidence of both HBV infection and cancer is common. The use of IST in patients with HBV can result in reactivation of HBV, which can, in turn, lead to significant morbidity and mortality. Although rates of HBV infection vary among populations, we feel that selective screening can miss a significant number of patients. We believe that our strategy of universal screening with HBsAg and anti-HBc prior to IST, followed by entecavir prophylaxis in all HBsAg-positive patients and selected HBsAg-negative/anti-HBc–positive patients, is effective and reasonable. Areas of uncertainty that require further investigation include evaluating the cost-effectiveness of universal pre-IST HBV screening, management of patients with solid tumors who are positive for anti-HBc only, and optimal duration of antiviral prophylaxis following completion of IST.

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article. 

 Ott JJ, Stevens GA, Groeger J, Wiersma ST. Global epidemiology of hepatitis B virus infection: new estimates of age-specific HBsAg sero-prevalence and endemicity. Vaccine. 2012;30:2212-9.

 Kim WR. Epidemiology of hepatitis B in the United States. Hepatology. 2009;49:S28-S34.

 Wasley A, Kruszon-Moran D, Kuhnert W, et al. The prevalence of hepatitis B virus infection in the United States in the era of vaccination. J Infect Dis. 2010;202:192-201.

 US Department of Health and Human Services. Action plan for the prevention, care, and treatment of viral hepatitis: updated, 2014-2016. 

http://aids.gov/pdf/viral-hepatitis-action-plan.pdf

 Weinbaum CM, Williams I, Mast EE, et al. Recommendations for identification and public health management of persons with chronic hepatitis B virus infection. MMWR Recomm Rep. 2008;57:1-20.

 National Cancer Institute. Lifetime risk of being diagnosed with cancer by site and race/ethnicity. 

http://seer.cancer.gov/csr/1975_2012/results_merged/topic_lifetime_risk.pdf

Lok AS, Liang RH, Chiu EK, et al. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology. 1991;100:182-8.

 Evens AM, Jovanovic BD, Su YC, et al. Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports. Ann Oncol. 2011;22:1170-80.

Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology. 2006;43:209-20.

Liu JY, Sheng YJ, Ding XC, et al. The efficacy of lamivudine prophylaxis against hepatitis B reactivation in breast cancer patients undergoing chemotherapy: a meta-analysis. J Formos Med Assoc. 2015;114: 164-73.

 National Comprehensive Cancer Network. Prevention and treatment of cancer-related infections. Version 1.2015. 

http://www.nccn.org/professionals/physician_gls/PDF/infections.pdf

Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009;50:661-2.

Hwang JP, Somerfield MR, Alston-Johnson DE, et al. Hepatitis B virus screening for patients with cancer before therapy: American Society of Clinical Oncology provisional clinical opinion update. J Clin Oncol. 2015;33:2212-20.

Oh MJ, Lee HJ. A study of hepatitis B virus reactivation associated with rituximab therapy in real-world clinical practice: a single-center experience. Clin Mol Hepatol. 2013;19:51-9.

 Koo YX, Tay M, Teh YE, et al. Risk of hepatitis B virus (HBV) reactivation in hepatitis B surface antigen negative/hepatitis B core antibody positive patients receiving rituximab-containing combination chemotherapy without routine antiviral prophylaxis. Ann Hematol. 2011; 90:1219-23.

 Hagiwara S, Sakurai T, Nishina S, et al. Characteristic pattern of reactivation of hepatitis B virus during chemotherapy for solid cancers. Dig Dis. 2012;30:541-6.

 Long M, Jia W, Li S, et al. A single-center, prospective and randomized controlled study: can the prophylactic use of lamivudine prevent hepatitis B virus reactivation in hepatitis B s-antigen seropositive breast cancer patients during chemotherapy? Breast Cancer Res Treat. 2011;127 :705-12.

 Kim EB, Kim DS, Park SJ, et al. Hepatitis B virus reactivation in a surface antigen-negative and antibody-positive patient after rituximab plus CHOP chemotherapy. Cancer Res Treat. 2008;40:36-8.

Dong HJ, Ni LN, Sheng GF, et al. Risk of hepatitis B virus (HBV) reactivation in non-Hodgkin lymphoma patients receiving rituximab-chemotherapy: a meta-analysis. J Clin Virol. 2013;57:209-14.

 Hammond SP, Borchelt AM, Ukomadu C, et al. Hepatitis B virus reactivation following allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant. 2009;15:1049-59.

Papamichalis P, Alexiou A, Boulbou M, et al. Reactivation of resolved hepatitis B virus infection after immunosuppression: is it time to adopt pre-emptive therapy? Clin Res Hepatol Gastroenterol. 2012;36:84-93.

 Yeo W, Chan TC, Leung NW, et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol. 2009;27:605-11.

Koo YX, Tan DS, Tan IB, et al. Hepatitis B virus reactivation and role of antiviral prophylaxis in lymphoma patients with past hepatitis B virus infection who are receiving chemoimmunotherapy. Cancer. 2010; 116:115-21.

 Matsue K, Kimura S, Takanashi Y, et al. Reactivation of hepatitis B virus after rituximab-containing treatment in patients with CD20-positive B-cell lymphoma. Cancer. 2010;116:4769-76.

 Kohrt HE, Ouyang DL, Keeffe EB. Systematic review: lamivudine prophylaxis for chemotherapy-induced reactivation of chronic hepatitis B virus infection. Aliment Pharmacol Ther. 2006;24:1003-16.

 Zachou K, Sarantopoulos A, Gatselis NK, et al. Hepatitis B virus reactivation in hepatitis B virus surface antigen negative patients receiving immunosuppression: a hidden threat. World J Hepatol. 2013;5:387-92.

 Yeo W, Ho WM, Hui P, et al. Use of lamivudine to prevent hepatitis B virus reactivation during chemotherapy in breast cancer patients. Breast Cancer Res Treat. 2004;88:209-15.

 Jang JW, Choi JY, Bae SH, et al. A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization. Hepatology. 2006;43:233-40.

 Dai MS, Wu PF, Lu JJ, et al. Preemptive use of lamivudine in breast cancer patients carrying hepatitis B virus undergoing cytotoxic chemotherapy: a longitudinal study. Support Care Cancer. 2004;12:191-6.

Lau GK, Yiu HH, Fong DY, et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology. 2003;125:1742-9.

Loomba R, Rowley A, Wesley R, et al. Systematic review: the effect of preventive lamivudine on hepatitis B reactivation during chemotherapy. Ann Intern Med. 2008;148:519-28.

 Papatheodoridis GV, Dimou E, Laras A, et al. Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease. Hepatology. 2002;36:219-26.

 Hsu C, Hsiung CA, Su IJ, et al. A revisit of prophylactic lamivudine for chemotherapy-associated hepatitis B reactivation in non-Hodgkin’s lymphoma: a randomized trial. Hepatology. 2008;47:844-53.

 Tan YW, Ye Y, Ge GH, et al. Natural YMDD-motif mutants affect clinical course of lamivudine in chronic hepatitis B. World J Gastroenterol. 2015;21:2089-95.

Huang H, Li X, Zhu J, et al. Entecavir vs lamivudine for prevention of hepatitis B virus reactivation among patients with untreated diffuse large B-cell lymphoma receiving R-CHOP chemotherapy: a randomized clinical trial. JAMA. 2014;312:2521-30.

Huang YH, Hsiao LT, Hong YC, et al. Randomized controlled trial of entecavir prophylaxis for rituximab-associated hepatitis B virus reactivation in patients with lymphoma and resolved hepatitis B. J Clin Oncol. 2013;31:2765-72.

US Food and Drug Administration. Boxed warning and new recommendations to decrease the risk of hepatitis B reactivation with the immune-suppressing and anti-cancer drugs Arzerra (ofatumumab) and Rituxan (rituximab). 

http://www.fda.gov/Drugs/DrugSafety/ucm366406.htm

The incidence of both hepatitis B virus infection and cancer is common. The use of immunosuppressive therapy in patients with hepatitis B virus can result in reactivation of hepatitis B virus, which can, in turn, lead to significant morbidity and mortality. 

Screening and Prevention of Hepatitis B Virus Reactivation During Chemotherapy

Exercise immunology has been a very lively field of research for the last few decades. Studies have focused on the apparent immunosuppressive effects of excessive exercise in elite athletes and the proposed immune-boosting effects of more moderate exercise in previously inactive individuals. Exercise studies with immunologic outcomes are less common in cancer populations, and the results of such studies have been inconclusive. This is likely due to small sample sizes, the use of different exercise regimens, heterogeneous patient populations, and differences between studies with regard to the immune markers under investigation and/or the assaying techniques used. In this review, Koelwyn and colleagues provide an overview of key studies in the field and a framework that highlights the critical steps at which exercise could modulate tumorigenesis; the framework can thus serve as a roadmap for future research.[1]

The authors propose a number of mechanisms by which exercise training can modulate the systemic host milieu, with particular reference to the inflammation-immune axis. However, the extent to which exercise per se, as opposed to exercise-induced changes in body composition, accounts for such changes remains unclear. A secondary analysis of data from early-stage breast cancer survivors who underwent a combined aerobic exercise and hypocaloric diet intervention suggests that weight loss (perhaps reflecting a reduction in body fat stores), rather than exercise per se, could be a more pronounced determinant of the observed changes in the systemic host milieu.[2] This is consistent with recent data from the SHAPE-2 trial, which show that the reduction in body fat stores resulting from an exercise program has a greater impact on circulating sex hormones (implicated in breast cancer) than exercise per se in overweight, insufficiently active postmenopausal women.[3] The independent effects of different doses of exercise on the inflammation-immune axis, as opposed to the effects of exercise-induced body composition changes, need to be more clearly delineated in future research.

With regard to exercise-induced changes in immune surveillance, Koelwyn et al cite studies in healthy populations that have reported acute and long-term changes in the number of circulating cells in specific immune cell populations and in the functioning of these cells. They show that data from the limited number of studies that have investigated the long-term effects of exercise on natural killer (NK) cell function in cancer patients are equivocal; this may be a reflection of the aforementioned methodologic differences between studies, not least of which are differences in the method of analysis (eg, chromium release assay vs flow cytometry). Additionally, immune cell function has typically been studied using in vitro techniques-and the in vitro environment is somewhat different from the in vivo environment, where different components of the innate and acquired immune system operate in concert. A key question is whether the acute effects of frequent exposure to exercise-induced demargination of leukocytes (eg, NK cells) from the blood vessel walls to the wider circulation, leading to a boost in the number of circulating cells but not necessarily to enhanced cellular function,[4] confers anticancer effects through multiple transient periods of augmented surveillance.

The authors then provide a compelling discussion of how changes in the tumor microenvironment could be influenced by exercise. This relatively unexplored area of research in human cancer patients clearly offers much potential for improving our understanding of how the immune system could be implicated in reported associations between physical activity and postdiagnosis survival. Preclinical animal studies demonstrate the impact of the tumor microenvironment on tumor-associated macrophages and neutrophils-and in particular, the role of tumor hypoxic regions in the conversion of these innate immune effector cells from antitumorigenic to immunosuppressive, protumorigenic phenotypes. Furthermore, murine studies suggest that exercise has the potential to attenuate the protumorigenic effects of hypoxic regions on infiltrating innate immune cells (perhaps by promoting microvascular changes), thereby retarding tumor progression. In the absence of human clinical studies, observational data provide indirect evidence of inhibited tumor progression in physically active men with clinically localized prostate cancer,[5] and of more regularly shaped blood vessels in the prostate tumors of men who engaged in brisk-pace walking before diagnosis,[6] which is consistent with this hypothesis. A limited number of investigations have focused on exercise as a modulator of the adaptive immune response in cancer, and further studies of exercise-induced changes in intratumoral dendritic cell antigen recognition and intratumoral T-cell phenotype and function are clearly warranted.

In conclusion, this insightful overview of current evidence shows how exercise at the right dosage could provide a potent stimulus for acute changes and long-term adaptations in numerous biological pathways that influence tumorigenesis. Sallis[7] pondered: “If we had a pill that conferred all the confirmed health benefits of exercise, would we not do everything humanly possible to see to it that everyone had access to this wonder drug? Would it not be the most prescribed pill in the history of mankind?” Over the last 10 years, since the seminal publication of Holmes et al in the 

Journal of the American Medical Association

,[8] a growing body of observational evidence has provided further support for an inverse association between postdiagnosis physical activity and disease recurrence, cancer-specific mortality, and/or overall mortality in cancer survivors. A deeper understanding of how exercise modulates the biological pathways of tumor progression would provide a more solid foundation for public health interventions aimed at primary and secondary cancer prevention, and could also inform novel pharmacologic therapies designed to target the same pathways.

The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article. 

 Koelwyn GJ, Wennerberg E, Demaria S, Jones LW. Exercise in regulation of inflammation-immune axis function in cancer initiation and progression. Oncology (Williston Park). 2015;29:908-20, 922.

 Scott E, Daley AJ, Doll H, et al. Effects of an exercise and hypocaloric healthy eating program on biomarkers associated with long-term prognosis after early-stage breast cancer: a randomized controlled trial. Cancer Causes Control. 2013;24:181-91.

 van Gemert WAM, Schuit AJ, van der Palen J, et al. Effect of weight loss, with or without exercise, on body composition and sex hormones in postmenopausal women: the SHAPE-2 trial. Breast Cancer Res. 2015;17:120.

 Simpson RJ, Kunz H, Agha N, Graff R. Exercise and the regulation of immune functions. Prog Mol Biol Transl Sci. 2015;135:355-80.

 Richman EL, Kenfield SA, Stampfer MJ, et al. Physical activity after diagnosis and risk of prostate cancer progression: data from the cancer of the prostate strategic urologic research endeavor. Cancer Res. 2011;71:3889-95.

 Van Blarigan EL, Gerstenberger JP, Kenfield SA, et al. Physical activity and prostate tumor vessel morphology: data from the Health Professionals Follow-up Study. Cancer Prev Res (Phila). 2015;8:962-7.

 Sallis RE. Exercise is medicine and physicians need to prescribe it! Br J Sports Med. 2009;43:3-4.

 Holmes MD, Chen WY, Feskanich D, et al. Physical activity and survival after breast cancer diagnosis. JAMA. 2005;293:2479-86.

Exercise at the right dosage could provide a potent stimulus for acute changes and long-term adaptations in numerous biological pathways that influence tumorigenesis.

New Insights Into the Immunomodulatory Effects of Exercise and Potential Impact on Tumorigenesis

During the past decade there has been substantial progress in the treatment of prostate cancer, resulting in the US Food and Drug Administration (FDA) approval of a number of life-prolonging therapeutics for patients with metastatic castration-resistant disease.[1] These accomplishments resulted from our enhanced understanding of the biological mechanisms of androgen receptor (AR) pathway activation, complex tumor microenvironment interaction of bone metastasis, antitumor immunology, and new oncogenic pathways. Taxanes represent the most active class of traditional chemotherapeutic agents for prostate cancer. Docetaxel is the first therapy that demonstrated survival benefit in the pivotal TAX 327 trial[2] and remains the first-line nonhormonal treatment of choice for metastatic castration-resistant prostate cancer (mCRPC). Cabazitaxel is another chemotherapeutic agent that showed survival benefit in patients who were previously treated with docetaxel,[3] and is currently approved for use in the second-line setting. Although great therapeutic advances have been made in mCRPC, the role of systemic approaches in the management of patients outside of mCRPC remains largely undefined.

In the article that accompanies this commentary, Drs. Lam and Flaig provide an excellent review on the role of chemotherapy in various stages of prostate cancer, with special emphasis on metastatic hormone-sensitive prostate cancer (mHSPC).[4] The authors conclude that current data support the use of upfront combined chemotherapy and androgen deprivation therapy (ADT) in properly selected patients with metastatic disease but not nonmetastatic/high-risk disease.

The authors provide a thorough discussion of three randomized phase III trials-CHAARTED, STAMPEDE, and GETUG-AFU 15, which evaluated the role of combined ADT/docetaxel in patients with mHSPC.[5-7] A significant prolongation of overall survival in favor of the combined approach was seen in the CHAARTED and STAMPEDE trials, with absolute benefits of 10 months or longer. Interestingly, a significant survival benefit was not observed in the GETUG-AFU 15 study. While the differences in outcomes between these trials remain unexplained, it is likely reflective of differences in patient populations. It is noteworthy that the survival in the ADT-alone control group of the GETUG-AFU 15 study is 54.2 months compared with 44 months on the CHAARTED study and 43 months on the STAMPEDE study, which suggests a difference in the distribution of elements of prognostic significance between the two positive studies and the GETUG-AFU 15 study populations (especially in terms of extent of disease). In addition, GETUG-AFU 15 is a smaller study, hence more follow-up time and number of events may be needed before final conclusions can be drawn. Although it appears clear, in our opinion, that all patients with newly diagnosed mHSPC should be offered a combined docetaxel/ADT treatment, there are a few questions that remain unclear. Perhaps the most important question is whether all patients, regardless of the extent of disease (high- vs low-volume), should be routinely offered the combined approach. This is particularly important in view of the stage migration affecting virtually all stages of prostate cancer. Most men with newly diagnosed prostate cancer at the present time are asymptomatic and have relatively low clinical disease burden, whereas the proportion of men presenting with higher-volume disease as defined on these studies is relatively small.[8] Evaluation of all mHSPC studies conducted over the past 3 decades indicates that overall survival figures have extended from 2.5 to almost 5 years with virtually the same ADT treatments employed. The main difference is a progressive increase in the proportion of patients with low disease burden in the most recent studies. The CHAARTED trial was initially designed to enroll patients with more than four bone and/or visceral lesions (high-volume disease). To increase enrollment, the study eligibility was later revised to include patients with any metastatic disease not meeting the original inclusion criteria (low-volume disease).[5] A post-hoc subgroup analysis of GETUG-AFU 15 that attempted to retrospectively classify the patients according to the CHAARTED criteria showed no significant difference in survival between high-volume and low-volume subgroups.[6] It is important to recognize that all extent-of-disease classifications employed in clinical trials conducted over the past 3 decades in mHSPC are primarily prognostic, to a great extent intuitive, and have not been adequately validated in terms of their relationship with treatment outcomes. Furthermore, none of these randomized trials were designed to specifically address the question of high- vs low-volume disease; therefore, specific therapeutic recommendations according to extent of disease cannot be made at this time. We feel the current data are sufficiently strong to allow physicians and patients to make sensible therapeutic choices. It is also important to recognize that other life-prolonging therapies, such as the novel AR-targeted drugs abiraterone and enzalutamide, are currently being evaluated in prospective randomized trials and may become part of the standard approach for patients with mHSPC.

The role of chemotherapy for patients with nonmetastatic relapsed (biochemically) disease and clinically high-risk localized disease remains undefined. Preliminary data on the patients with high-risk localized disease in the STAMPEDE trial showed a significant relapse-free survival (RFS) benefit with the addition of docetaxel, but no overall survival benefit. Similarly, the recently published GETUG 12 trial demonstrated RFS improvement with the addition of docetaxel and estramustine to ADT in patients with high-risk localized disease, but the survival analysis has not yet been reported.[9] Preliminary reports of the Radiation Therapy Oncology Group (RTOG) 0521 study showed that the addition of docetaxel to adjuvant ADT/radiation resulted in an absolute benefit of 4% in 4-year overall survival compared with ADT/radiation alone.[10] However, the survival improvement in this study did not meet its prestated survival criteria; in addition, the study is criticized for its design, which used a one-sided statistical analysis. At this time, there is no definitive data to support the use of chemotherapy in patients with M0 disease.

Historically, clinical trials of biochemically relapsed and locally advanced disease have faced significant challenges. Lack of consensus on study design, patient and treatment selection, lack of validated study endpoints, evolving competitive standard and research approaches, long follow-up time required, and need for substantial research support are among the obstacles that the research community has faced in conducting trials in this paradigm. The results in mHSPC would strongly argue in favor of vigorous exploration of the role of taxane-based chemotherapy outside the metastatic paradigm.

 Park JC, Eisenberger M. Advances in the treatment of metastatic prostate cancer. Mayo Clinic Proceedings. 2015. (In press)

 Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502-12.

 de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147-54.

 Lam ET, Flaig TW. Upfront chemotherapy for metastatic prostate cancer. Oncology (Williston Park). 2015;29:956-62.

 Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373:737-46.

 Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14:149-58.

 James ND, Sydes MR, Mason MD, et al. Docetaxel and/or zoledronic acid for hormone-naive prostate cancer: First overall survival results from STAMPEDE (NCT00268476). J Clin Oncol. 2015;33(suppl):abstr 5001.

 Tangen CM, Hussain MH, Higano CS, et al. Improved overall survival trends of men with newly diagnosed M1 prostate cancer: a SWOG phase III trial experience (S8494, S8894 and S9346). J Urol. 2012;188:1164-9.

 Fizazi K, Faivre L, Lesaunier F, et al. Androgen deprivation therapy plus docetaxel and estramustine versus androgen deprivation therapy alone for high-risk localised prostate cancer (GETUG 12): a phase 3 randomised controlled trial. Lancet Oncol. 2015;16:787-94.

 Sandler HM, Hu C, Rosenthal SA, et al. A phase III protocol of androgen suppression (AS) and 3DCRT/IMRT versus AS and 3DCRT/IMRT followed by chemotherapy (CT) with docetaxel and prednisone for localized, high-risk prostate cancer (RTOG 0521). J Clin Oncol. 2015;33(suppl):abstr LBA5002.

Although great therapeutic advances have been made in metastatic castration-resistant prostate cancer, the role of systemic approaches in the management of patients outside of metastatic castration-resistant prostate cancer remains largely undefined.

Chemotherapy in Prostate Cancer Beyond Metastatic CRPC

Radiologic screening for lung cancer had a long and unsuccessful history until the advent of low-dose computed tomography (CT) screening and the completion of the National Lung Screening Trial (NLST), which demonstrated an improvement in lung cancer–specific mortality in a high-risk population.[1] This screening modality is now largely accepted in the United States and is reimbursed under Medicare and most commercial insurance plans.

Most pulmonary lesions found during screening are not malignant. Expansion of the NLST eligibility criteria would result in more lung cancers detected in the United States but would require the screening of many more people to do so. Concerns about screening include overdiagnosis, overtreatment, and harm caused by procedures for benign lesions, as well as questions about the cost-effectiveness of this approach. Specifically, it is not known whether the NLST results will be reproduced when screening is conducted across the United States outside the rigor of a clinical trial.

In this issue of ONCOLOGY, Kamel and colleagues provide a useful overview of the surgical issues raised by lung cancer screening.[2] Among the most important is the involvement of thoracic surgeons in the design and quality analyses of CT screening programs. This has been the approach at many academic centers, including ours, and leads to a multidisciplinary commitment to screening, which helps ensure smooth operations, appropriate marketing, good data acquisition, and appropriate quality review.

The authors stress the need for diagnostic and therapeutic algorithms within screening programs to ensure consistency and reduce unnecessary procedures and cost. One assumption underlying this recommendation is that the screened population is substantially subject to management by a particular healthcare system-an assumption at odds with the patchwork nature of American healthcare and the considerable mobility of our population. Medicare’s requirements for eligibility, uniform radiographic reporting, data collection, and registry participation do provide a strong incentive for national standardization, which ought to minimize ad hoc management of patients with screen-detected lung nodules.

When suspicious lesions are identified, minimally invasive approaches to diagnosis and treatment-which have very low morbidity-are preferable. As Kamel et al point out, surgeons should be certified in thoracic surgery and adept at minimally invasive approaches. Moreover, surgeons and pulmonologists consulted for screen-positive cases must be willing to observe some lesions that are not amenable to biopsy, such as deep small nodules and multiple ground-glass opacity lesions, or lesions that are biopsy-negative and not suitable for simple wedge resection. Although the authors cite excellent diagnostic yield from fine-needle aspiration in high-volume centers, it is not clear that such yields can be replicated in the broader medical community, where most patients are evaluated and treated.

The role of sublobar resection for small peripheral tumors is being defined by the trials described by Kamel et al, but also, in my opinion, by tacit adoption of smaller resection for these lesions ahead of confirmatory prospective clinical trial results. This trend coincides with the gradual maturation of experience in the use of stereotactic body radiation therapy (SBRT) for small lung tumors, an alternative to the sublobar approach. As we move forward, the increased incidence of small screen-detected lung cancers will undoubtedly be accompanied by vigorous debate, hopefully bolstered by prospective trial data, over the role of SBRT vs sublobar resection as primary therapy.

Finally, we must embrace the essential work of primary care providers in lung cancer screening, a role they already play in colon and breast cancer screening. Discussion of screening should go hand in hand with consistent provision of smoking cessation resources, a task for primary care providers and specialists alike. For those launching screening programs, support for and from primary care networks is critical to sustained success.

In the long run, lung cancer screening will be seen as a primary care function that feeds multidisciplinary specialty programs for interpretation, surveillance, diagnosis, and treatment. Without both primary and specialty care arms, applied nationally and well, the promise of CT screening for lung cancer will not translate into meaningful improvement in public health.

The author has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article

 Aberle DR, Adams AM, Berg CD, et al. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409.

 Kamel M, Stiles B, Altorki N. Clinical issues in the surgical management of screen-identified lung cancers. Oncology (Williston Park). 2015;29:944-49, 951.

Radiologic screening for lung cancer had a long and unsuccessful history until the advent of low-dose computed tomography (CT) screening and the completion of the National Lung Screening Trial, which demonstrated an improvement in lung cancer–specific mortality in a high-risk population.

CT Screening for Lung Cancer: How to Fulfill the Promise

In this issue of ONCOLOGY, Dr. Tchekmedyian and colleagues provide a comprehensive overview of many of the novel combinations of immunotherapeutic agents under development for the treatment of various tumor types.[1] They present a clear conceptual framework for understanding different immunotherapy strategies, and highlight the complexity of immunotherapy by illustrating the vast array of immune-based and non–immune-based approaches that can enhance the antitumor immune response-including checkpoint inhibitors, vaccines, chemotherapy, small molecules, T-cell engineering, and radiotherapy. With a staggering number of agents and combinations under investigation, a rational approach is essential to prioritize the best treatments for individual patients and specific tumor types.

In view of the potential for durable responses with immunotherapy, it will be important to identify the most effective and least toxic regimens for individual patients.